Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population

Abstract

Leprosy is a chronic infectious disease, caused by Mycobacterium leprae, which affects skin and peripheral nerves. Polymorphisms in genes associated with autophagy, metabolism, innate and adaptive immunity confer susceptibility to leprosy. However, these associations need to be confirmed through independent replication studies in different ethnicities. The population from Amazon state (northern Brazil) is admixed and it contains the highest proportion of Native American genetic ancestry in Brazil. We conducted a case-control study for leprosy in which we tested fourteen previously associated SNPs in key immune response regulating genes: TLR1 (rs4833095), NOD2 (rs751271, rs8057341), TNF (rs1800629), IL10 (rs1800871), CCDC122/LACC1 (rs4942254), PACRG/PRKN (rs9356058, rs1040079), IFNG (rs2430561), IL6 (rs2069845), LRRK2 (rs7298930, rs3761863), IL23R (rs76418789) and TYK2 (rs55882956). Genotyping was carried out by allelic discrimination in 967 controls and 412 leprosy patients. Association with susceptibility was assessed by logistic regression analyses adjusted for the following covariates: gender, age and ancestry. Genetic ancestry was similar in case and control groups. Statistically significant results were only found for IFNG and NOD2. The rs8057341 polymorphism within NOD2 was identified as significant for the AA genotype (OR = 0.56; 95% CI, 0.37–0.84; P = 0.005) and borderline for the A allele (OR = 0.76; 95% CI, 0.58–1.00; P = 0.053) and carrier (OR = 0.76; 95% CI, 0.58–1.00; P = 0.051). The rs2430561 SNP in IFNG was associated with disease susceptibility for the AT genotype (OR = 1.40; 95% CI, 1.06–1.85; P = 0.018) and carrier (OR = 1.44; 95% CI, 1.10–1.88; P = 0.008). We confirmed that NOD2 and IFNG are major players in immunity against M. leprae in the Amazon ethnic admixed population.

Author summary

Leprosy is chronic infectious diseases caused by Mycobacterium leprae that affect the skin and peripheral nerves. The incidence is still high where approximately 200,000 new cases are diagnosed each year. There is no clear sign for early diagnosis and transmission is likely to occur before treatment, which, irrespective of its success, has not hampered stationary incidence in the past 20 years. Thus, there is pressing need for markers that discriminate exposure, infection and disease in order to better detect leprosy progression, control transmission and prevent disabilities. Here, we investigated whether polymorphisms located in eleven genes are associated to leprosy in a population from Amazon state (northern Brazil) which is admixed and it contains the highest proportion of Native American genetic ancestry in Brazil. We validated NOD2 and IFNG associations with resistance and risk of leprosy, respectively, in the Amazon ethnic admixed population. Genetic patterns of leprosy susceptibility could have an impact on the prognosis of individuals that are more likely to develop the disease (among household contacts, for example). Therefore, this strategy could identify high-risk individuals prone for prophylactic measures such as treatment with single-dose rifampicin and BCG vaccination.